Review of TFEB-amplified renal cell carcinoma with focus on clinical and pathobiological aspects

Introduction

Peckova et al. first described a case of TFEB-amplified renal cell carcinoma (RCC) in 2014 [1]. Since then, approximately 42 cases with such features have been reported [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. To date, there seems to be a difference in the clinicopathological aspect between TFEB-translocation RCC and TFEB-amplified RCC. In this article, we review TFEB-amplified RCC with a special reference to clinical and pathobiological aspects.

Clinical characteristics

The 42 patients consisted of 24 males and 18 females [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. The age of patients ranged from 28 to 83 years with a mean age of 62.8 years [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14].

Pathological findings

Macroscopic findings

The tumor size was available in 41 cases. The size of the tumor ranged from 1.9 to 19.5 cm with a mean size of 8.7 cm [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. Tumor thrombosis was identified in four cases [3, 8].

Microscopic findings

The tumor demonstrated a variety of architectural patterns such as solid, alveolar, papillary, pseudopapillary, nested or tubular (Fig. 1A). ISUP grade usually corresponds to grade 3 or 4 [1, 3, 4, 8, 11]. Cytomorphology shows eosinophilic, clear, amphophilic or even oncocytic cytoplasm [2, 8, 14]. Cytoplasmic eosinophilia seems to be more frequent in TFEB-amplified RCC than TFEB-translocation RCC (Fig. 1B) [14]. The biphasic growth pattern consisting of large and small neoplastic cells is characteristic of TFEB-translocation RCC, but this pattern seems to be less frequent in TFEB-amplified RCC [14]. Rarely, cases with grade 2 have been reported [11, 14]. Necrosis can be frequently observed [1, 3, 5, 8]. Hemorrhage may be observed in some cases. Sarcomatoid change has been reported [14].

Immunohistochemical findings

Neoplastic cells with TFEB-amplified RCC show diffuse or patchy positivity for TFEB. However, some tumors may be completely negative or show lower level expression than TFEB-translocation RCC [14]. TFE3 is negative in most cases. Most tumors are diffusely or patchily positive for melan-A. The positivity for cathepsin-K is various.

Molecular genetic findings

Fluorescence in situ hybridization (FISH) frequently shows amplification of more than 10 or 20 copies of the TFEB gene (Fig. 1). However, cases with low-amplification of the TFEB gene have also been described. This tumor may be associated with translocation of the TFEB gene in some cases or not in other cases. Namely, RCC with immunohistochemical positivity of TFEB protein is divided into three categories, namely RCC with translocation of the TFEB gene, RCC with amplification of the TFEB gene, and RCC with translocation as well as amplification of the TFEB gene. Co-amplification of the VEGFRA gene located in the chromosome region 6p21.1 has been described in most cases [5, 7, 11, 12, 14]. Co-amplification of the RUNX2 gene or CCND3 gene has also been described [11, 14]. Chromosomal abnormalities have been identified in eight cases [4, 8]. Using array comparative genomic hybridization method, gains of chromosome 6p or chromosome 2q were observed in six and four cases, respectively [4, 8]. Loss of chromosome 3p has been identified in seven cases [4, 8]. Gain of chromosome 7 or chromosome 17 has been described [4]. Among them, seven tumors involved the VHL gene locus [4, 8]. Point mutation of the TP53 or CDKN2A gene has been reported in TFEB-amplified RCC [8].

Differential diagnosis

The original diagnosis includes various histologic subtypes such as clear cell RCC, papillary RCC, translocation RCC, unclassified RCC or RCC with sarcomatoid change [8]. Accordingly, these diseases should be distinguished from TFEB-amplified RCC. The distinction from epithelioid angiomyolipoma is also important [2]. Pathologists need to note that some molecular genetic studies such as loss of chromosome 3p or gain of chromosome 7 or 17 may not be available in the distinction from clear cell RCC or papillary RCC [4].

Therapy

As co-amplification of the VEGFRA gene has been frequently reported in TFEB-amplified RCC, VEGF may become a therapeutic target [5, 7, 11, 12]. Radiation therapy has been tried previously [2].

Prognosis

Most TFEB-amplified RCCs behave in an aggressive fashion [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. The 5-year survival rate is estimated to be 48% [11]. Metastasis frequently occurs in this tumor. Metastatic sites include lung, heart, bone, liver and colon [2, 8, 9].

Future perspectives

TFEB-amplified RCC seems to be characterized by papillary/pseudopapillary architecture, frequent necrosis, high nuclear grade and aggressive clinical behavior with frequent distant metastasis. The copy number of TFEB gene amplification in previously reported TFEB-amplified RCCs has varied from case to case. Therefore, whether the copy number of the TFEB gene has a significant impact on prognosis of TFEB-amplified RCC or not requires further examination.

The authors declare no conflict of interest.

References